The selective synthesis of stereogenic metal centers is less developed than carbon stereogenic centers. The first synthesis of a stereogenic metal complex, 1, was accomplished in 1911. As shown in FIG. 1, complex 1 is chiral due to the arrangement of the two bidentate ethylenediamine ligands; the complex is prepared as a racemic mixture and the enantiomers separated by classical resolution.
Other complexes comprising a stereogenic metal center have also been stereoselectively synthesized using chiral polydentate ligands, sometimes in conjunction with at least one achiral ligand. One such example is complex 2, shown in FIG. 1. A class of Ru-based olefin metathesis catalysts containing a stereogenic metal center and synthesized using a chiral bidentate ligand has been reported, including structures 3 and 4 shown in FIG. 1. Using this method, a single diastereomer can be isolated in high yield. In some cases, a preference for the formation of a particular diastereomer can be attributed to steric factors.
Additionally, there are a number of stereogenic-at-metal complexes bearing achiral polydentate ligands, where stereochemistry at the metal center can be partially controlled by means of a chiral monodentate ligand. For example, FIG. 2 shows the transformation of a racemic Ru complex 5 to complex 6 through a dynamic enantioselective process upon reaction with an enantiopure sulfoxide. The reaction proceeded in high yield and with modest diastereoselectivity (74% d.e.). It has also been shown that the chloride and sulfoxide ligands of complexes such as 6 may be displaced by an additional bipyridyl ligand with retention of configuration, thus generating an enantioenriched chiral complex bearing only achiral ligands.
Although less common, the stereoselective self-assembly of achiral polydentate ligands about a metal center has also been controlled by means of a chiral counterion. For example, an octahedral Fe complex has been synthesized, bearing a bidentate and a tetradentate ligand, with high selectivity (>20:1 d.r.) by means of a P stereogenic phosphate counterion (trisphat).
Examples of stereogenic metal complexes, bearing all monodentate ligands, however, are rare, and generally have been prepared only in racemic form. FIG. 3 shows examples of such metal complexes. One of the challenges faced when preparing enantiopure stereogenic metal complexes with all monodentate ligands is the ability of many of these ligands, leading to racemization of the complex. In addition, the complexes often require a separate purification step in order to separate the enantiomers and/or diastereomers. Re complex 7, shown in FIG. 4, is a “piano stool” complex, which is stereogenic at the metal (but racemic) and carries all monodentate ligands. One of the ligands in the complex is an alkoxide. As shown by the synthesis in FIG. 4, this complex may be reacted with HBF4.OEt2 to generate cationic complex 8, which contains a datively-bound alcohol ligand; several complexes of this type have been reported.
Another example of an enantioselective synthesis of complex having a stereogenic metal center and bearing only monodentate ligands is shown in FIG. 5. However, diastereomers formed from the reaction of Na mentholate with racemic complex 9 were separated by crystallization. Saponification was performed to regenerate complex 9, now enantioenriched, whose only stereogenic element is the metal center. Prochiral complexes, such as 10, can be desymmetrized by displacement of one of the carbonyl ligands with a chiral monodentate phosphine, as shown in FIG. 6. The reaction was not stereoselective and the two diastereomers generated, 11a and 11b, were separated by chromatography or fractional crystallization. It should also be noted that “piano stool” complexes, such as complexes 7-11, have an octahedral geometry (i.e. they are not tetrahedral).
Complexes 13-15, as shown in FIG. 3, are olefin metathesis catalysts. Complexes 14-15, as well as Re complex 7, are stereogenic metal complexes with an alkoxide ligand, however, all of these complexes comprise of racemic mixtures. Complex 14 has shown unique reactivity for enyne metathesis.
Previous studies have focused on the use of chiral, terpene-derived, alcohols for stereoselective synthesis of tetrahedral Mo alkylidenes. Generally, Mo monoalkoxide complexes are generated as a 1:1 mixture of diastereomers. Additionally, reaction of many alcohols with Mo bis(pyrrolide) complexes may result in substitution of both pyrrolide ligands to generate a bis(alkoxide) complex (e.g., Mo is not a stereogenic center). However, FIG. 7 shows the reaction of Mo bis(pyrrolide) 16a with one equivalent of borneol 17, resulting in the generation of monoalkoxide complex 18 with 3:1 diastereoselectivity.
Chiral ligands typically used for enantioselective Mo-catalyzed olefin metathesis have been diols derived from BINOL or a chiral biphenol, as shown in FIG. 8.
The use of a chiral alcohol in enantioselective catalysis has been attempted before. For example, a mono-protected BINOL derivative was employed in a Brønsted acid-catalyzed enantioselective Morita-Baylis-Hillman reaction, as shown in FIG. 9A. The catalysts were relatively unreactive (up to 43% yield) and the products racemic; chiral diols proved to be more reactive and selective catalysts. Monodentate alcohols have also been used in the synthesis of organometallic compounds, as shown in FIG. 9B.
In some cases, it may be desirable to utilize a chiral metal complex having a stereogenic metal center. However, there are often challenges associated with synthesizing and/or utilizing such metal complexes. For example, the stereoselective synthesis of metal complexes having a stereogenic metal center has been shown to be difficult. Also, such metal complexes have exhibited stereomutation at the metal center and/or loss of stereochemistry due to labile ligands. For example, in an olefin metathesis cycle, the metal center may undergo “inversion” or racemization by non-productive olefin metathesis.
Accordingly, improved compositions and methods are needed.